PROJECT SUMMARY Poorly treated pain in older adults with Alzheimer's disease (AD) is a critical public health problem and understanding sex and AD-related differences in pain function is an NIA priority area. When compared to healthy adults, and in the presence of similarly known painful conditions, older adults with AD receive less pain medication. Reasons for this discrepancy are poorly understood. Inadequately treated pain negatively impacts quality of life and increases health care costs. It is well documented that cognitively healthy males and females experience and report acute and chronic pain differently, however it is unknown if these differences extend into the population of older adults with AD. Determining the biological reasons for sex-differences leading to alterations in pain processing is essential for increasing our understanding of pain in older adults with AD. In response to pain, evidence suggests that brain structure and brain function differ by sex and may be altered in AD. However, it is unknown how these structural and functional nervous system alterations differ by sex and how AD impacts psychophysical and neurophysiological responses to pain. The proposed research in this R01 application will examine how verbal pain reporting patterns in responses to acute experimental thermal pain differs between older males and females with and without AD and how these sex-differences map onto regional and network brain functional changes. Experimental acute thermal pain delivery predicts well the response to painful medical conditions. We propose to examine the psychophysical and neurophysiological response to experimental thermal stimuli between healthy males and females (aged 65 or older) and aged match males and females with AD (aged 65 or older). The aims of this study are to determine whether sensory (stimulus intensity) and affective (stimulus unpleasantness) responses differ by sex in people with and without AD during cutaneous thermal stimulation. We hypothesize that AD will be associated with an increased sensitivity in females yet males with AD will experience greater unpleasantness with pain. These changes may arise from AD-associated changes in brain structure and function as well as from sex-specific alterations in pain-related brain networks. Examining baseline differences in experimental thermal pain between males and females with and without AD will provide a foundation for understanding factors that may contribute to untreated pain risk, as well as for developing sex- specific novel assessment, prevention, and treatment strategies in the older population with AD.